Venkateswar Jarugula

Clinical Pharmacokinetics and Pharmacodynamics of Aliskiren

Aliskiren is the first orally bioavailable direct renin inhibitor approved for the treatment of hypertension. It acts at the point of activation of the renin-angiotensin-aldosterone system, or renin system, inhibiting the conversion of angiotensinogen to angiotensin I by renin and thereby reducing the formation of angiotensin II by angiotensin-converting enzyme (ACE) and ACE-independent pathways. Aliskiren is a highly potent inhibitor of human renin in vitro (concentration of aliskiren that produces 50% inhibition of renin 0.6 nmol/L). Aliskiren is rapidly absorbed following oral administration, with maximum plasma concentrations reached within 1–3 hours. The absolute bioavailability of aliskiren is 2.6%. The binding of aliskiren to plasma proteins is moderate (47–51%) and is independent of the concentration. Once absorbed, aliskiren is eliminated through the hepatobiliary route as unchanged drug and, to a lesser extent, through oxidative metabolism by cytochrome P450 (CYP) 3A4. Unchanged aliskiren accounts for approximately 80% of the drug in the plasma following oral administration, indicating low exposure to metabolites. The two major oxidized metabolites of aliskiren account for less than 5% of the drug in the plasma at the time of the maximum concentration. Aliskiren excretion is almost completely via the biliary/faecal route; 0.6% of the dose is recovered in the urine. Steady-state plasma concentrations of aliskiren are reached after 7–8 days of once-daily dosing, and the accumulation factor for aliskiren is approximately 2. After reaching the peak, the aliskiren plasma concentration declines in a multiphasic fashion.No clinically relevant effects of gender or race on the pharmacokinetics of aliskiren are observed, and no adjustment of the initial aliskiren dose is required for elderly patients or for patients with renal or hepatic impairment. Aliskiren showed no clinically significant increases in exposure during coadministration with a wide range of potential concomitant medications, although increases in exposure were observed with P-glycoprotein inhibitors. Aliskiren does not inhibit or induce CYP isoenzyme or P-glycoprotein activity, although aliskiren is a substrate for P-glycoprotein, which contributes to its relatively low bioavailability.Aliskiren is approved for the treatment of hypertension at once-daily doses of 150 mg and 300 mg. Phase II and III clinical studies involving over 12 000 patients with hypertension have demonstrated that aliskiren provides effective long-term blood pressure (BP) lowering with a good safety and tolerability profile at these doses. Aliskiren inhibits plasma renin activity (PRA) by up to 80% following both single and multiple oral-dose administration. Similar reductions in PRA are observed when aliskiren is administered in combination with agents that alone increase PRA, including diuretics (hydrochlorothiazide, furosemide [frusemide]), ACE inhibitors (ramipril) and angiotensin receptor blockers (valsartan), despite greater increases in the plasma renin concentration. Moreover, PRA inhibition and BP reductions persist for 2–4 weeks after stopping treatment, which is likely to be of benefit in patients with hypertension who occasionally miss a dose of medication.Preliminary data on the antiproteinuric effects of aliskiren in type 2 diabetes mellitus suggest that renoprotective effects beyond BP lowering may be possible. Further studies to evaluate the effects of aliskiren on cardiovascular outcomes and target organ protection are ongoing and will provide important new data on the role of direct renin inhibition in the management of hypertension and other cardiovascular disease.

The IQ‐CSRC Prospective Clinical Phase 1 Study: “Can Early QT Assessment Using Exposure Response Analysis Replace the Thorough QT Study?”

A collaboration between the Consortium for Innovation and Quality in Pharmaceutical Development and the Cardiac Safety Research Consortium has been formed to design a clinical study in healthy subjects demonstrating that the thorough QT (TQT) study can be replaced by robust ECG monitoring and exposure–response (ER) analysis of data generated from First‐in‐Man single ascending dose (SAD) studies. Six marketed drugs with well‐characterized QTc effects were identified in discussions with FDA; five have caused QT prolongation above the threshold of regulatory concern. Twenty healthy subjects will be enrolled in a randomized, placebo‐controlled study designed with the intent to have similar power to exclude small QTc effects as a SAD study. Two doses (low and high) of each drug will be given on separate, consecutive days to 9 subjects. Six subjects will receive placebo. Data will be analyzed using linear mixed‐effects ER models. Criteria for QT‐positive drugs will be the demonstration of an upper bound (UB) of the 2‑sided 90% confidence interval (CI) of the projected QTc effect at the peak plasma level of the lower dose above the threshold of regulatory concern (currently 10 ms) and a positive slope of ER relationship. The criterion for QT‐negative drug will be an UB of the CI of the projected QTc effect of the higher dose <10 ms. It is expected that a successful outcome in this study will provide evidence supporting replacement of the TQT study with ECG assessments in standard early clinical development studies for a new chemical entity.

Effect of Cyclosporine on the Pharmacokinetics of Aliskiren in Healthy Subjects

To explore the clinical relevance of inhibition of multidrug resistance transporter 1 and organic anion transporting polypeptide transporter, a drug—drug interaction study was conducted using aliskiren and cyclosporine. This was an open‐label, single‐sequence, parallel‐group, single‐dose study in healthy subjects. Subjects (n = 14) first received aliskiren 75 mg orally (period 1), followed by aliskiren 75 mg + cyclosporine 200 mg (period 2) after a 7‐day washout period, and aliskiren 75 mg + cyclosporine 600 mg (period 3) after a 14‐day washout period. Safety and pharmacokinetics were analyzed during each period. The primary objective was to characterize pharmacokinetics of aliskiren (single‐dose and combination with cyclosporine). The increases in area under the time—concentration curve from time 0 to infinity and maximum concentration associated with cyclosporine 200 mg or 600 mg were 4‐ to 5‐fold and 2.5‐fold, respectively. Mean half‐life increased from 25 to 45 hours. Based on comparison to literature, a single‐dose of aliskiren 75 mg did not alter the pharmacokinetics of cyclosporine. Aliskiren 75 mg was well tolerated. Combination with cyclosporine increased the number of adverse events, mainly hot flush and gastrointestinal symptoms, with no serious adverse events. Two adverse events led to withdrawal (ligament rupture, not suspected to be study‐drug related; and vomiting, suspected to be study‐drug related). Laboratory parameters, vital signs, and electrocardiographs showed no time‐ or treatment‐related changes. As cyclosporine significantly altered the pharmacokinetics of aliskiren in humans, its use with aliskiren is not recommended.

Influence of Body Weight and Gender on the Pharmacokinetics, Pharmacodynamics, and Antihypertensive Efficacy of Aliskiren

Gender and body weight influence the pharmacokinetics and pharmacodynamics of many drugs. This pooled analysis of 17 clinical studies evaluated the effect of gender, body mass index (BMI), body weight, and lean body weight (LBW) on the pharmacokinetics of the direct renin inhibitor aliskiren in healthy volunteers (n = 392). A separate pooled analysis of 5 clinical studies in patients with hypertension (n = 2327) assessed the influence of gender and BMI on the effects of aliskiren on plasma renin activity and blood pressure. Area under the aliskiren plasma concentration‐time curve (AUCτ) was 22% lower and the peak aliskiren plasma concentration (Cmax) was 24% lower in men than women (P < .05). BMI was not significantly correlated with AUCτ (r = 0.005; P = .917); AUCτ was negatively correlated with body weight (r = −0.235; P < .0001) and LBW (r = −0.295; P < .0001). Results were similar for Cmax. Adjusting individual aliskiren AUCτ and Cmax values for overall mean body weight or LBW abolished gender differences. Based on r2 values, LBW variation accounted for 8.9% of aliskiren AUCτ variation. In patients with hypertension, gender and BMI did not significantly influence the effects of aliskiren on plasma renin activity or blood pressure. It was concluded that lower systemic exposure to aliskiren in men versus women relates to differences in body weight; neither gender nor body weight has clinically relevant effects on the pharmacokinetics or pharmacodynamics of aliskiren.

Effect of Verapamil on the Pharmacokinetics of Aliskiren in Healthy Participants

The authors describe the drug‐drug interaction between aliskiren and verapamil in healthy participants. Eighteen participants first received an oral dose of aliskiren 300 mg (highest recommended clinical dose) in period 1. After a 10‐day washout period, the participants received verapamil 240 mg/d for 8 days (period 2). On day 8, the participants also received an oral dose of aliskiren 300 mg. Safety and pharmacokinetic analyses were performed during each treatment period. Concomitant administration of a single dose of aliskiren during steady‐state verapamil resulted in an increase in plasma concentration of aliskiren. The mean increase in AUC0‐∞, AUClast, and Cmax was about 2‐fold. On day 8, in the presence of aliskiren, AUCτ,ss of R‐norverapamil, R‐verapamil, S‐norverapamil, and S‐verapamil was decreased by 10%, 16%, 10%, and 25%, respectively. Similarly, the Cmax,ss of R‐norverapamil, R‐verapamil, S‐norverapamil, and S‐verapamil was decreased by 13%, 18%, 12%, and 24%, respectively. Aliskiren did not affect the AUCτ,ss ratios of R‐norverapamil/R‐verapamil and S‐norverapamil/S‐verapamil. Aliskiren administered alone or in combination with verapamil was well tolerated in healthy participants. In conclusion, no dose adjustment is necessary when aliskiren is administered with moderate ABCB1 inhibitors such as verapamil (240 mg/d).

Evaluation of Pharmacokinetic Interactions Between Amlodipine, Valsartan, and Hydrochlorothiazide in Patients With Hypertension

The steady‐state pharmacokinetic (PK) interaction potential between amlodipine (10 mg), valsartan (320 mg), and hydrochlorothiazide (HCTZ; 25 mg) was evaluated in patients with hypertension in a multicenter, multiple‐dose, open‐label, 4‐cohort, parallel‐group study. Eligible patients were randomly allocated to the dual combination of valsartan + HCTZ, amlodipine + valsartan, or amlodipine + HCTZ and nonrandomly allotted to amlodipine + valsartan + HCTZ triple combination treatment. After 6 days of treatment with a half‐maximal dose of different combinations, patients were up‐titrated to the maximal drug doses from day 7 through day 17. PK parameters of corresponding analytes from the triple‐ and dual‐treatment groups were estimated on day 17 and compared. Safety and tolerability of all treatments was assessed. The Cssmax and AUC0‐τ values of amlodipine or HCTZ remained unaffected when administered with valsartan + HCTZ or valsartan + amlodipine, respectively. On the other hand, valsartan exposure increased by 10% to 25% when coadministered with HCTZ and amlodipine, which is not considered clinically relevant. In conclusion, there were no clinically relevant PK interactions with amlodipine, valsartan, and HCTZ triple combination compared with the corresponding dual combinations. All treatments were safe and well tolerated.

Pharmacokinetics, safety and tolerability of single and multiple oral doses of aliskiren in healthy Chinese subjects: a randomized, single-blind, parallel-group, placebo-controlled study.

AbstractBackground: Aliskiren is the first oral direct renin inhibitor to be approved for the treatment of hypertension. The pharmacokinetic and pharmacodynamic profile of aliskiren has been extensively characterized in Caucasian individuals; however, drug disposition, treatment response and tolerability can vary among ethnic groups, and these variations are difficult to predict. Objective: To evaluate the single- and multiple-dose pharmacokinetics of aliskiren in healthy Chinese subjects. Methods: This was a randomized, single-blind, parallel-group, placebo-controlled study. On day −1, subjects were randomized to one of four cohorts (aliskiren 75, 150, 300 or 600 mg). On day 1, eight individuals in each cohort received a single dose of active treatment and two received placebo. Subjects randomized to aliskiren 300 mg received additional once-daily doses on days 5–11 to establish steady-state pharmacokinetics. Subjects receiving aliskiren 75, 150 or 600 mg (cohorts 1, 2 and 4) completed the study at the end of the 96-hour pharmacokinetic assessment period. Subjects receiving aliskiren 300 mg (cohort 3) had additional pharmacokinetic assessments on days 5–15. The study was carried out at the Peking Union Medical College Hospital, Beijing, China, and included 40 healthy Chinese subjects. The main outcome measures were the pharmacokinetic parameters for aliskiren, including area under the plasma concentration-time curve from time zero to infinity (AUC∞) and maximum plasma concentration (Cmax). Results: Aliskiren AUC∞ and Cmax increased greater than proportionally across the 8-fold dose range (75–600 mg; mean AUC∞ 291-4726 ng· h/mL, mean Cmax 62–699 ng/mL), but a dose-proportional 2-fold increase was observed within the clinically approved dose range (150–300 mg; mean AUC∞ 876–1507 ng· h/mL, mean Cmax 137–271 ng/mL). At steady state, the mean AUC during the dosage interval (AUCτ) for aliskiren 300 mg (1532 ± 592 ng · h/mL) was similar to the AUC∞ observed following a single dose. Conclusion: Aliskiren exhibits similar single-dose and steady-state pharmacokinetics in Chinese subjects compared with those observed in Caucasian individuals in previous studies.

An Exposure-Response Modeling Approach to Examine the Relationship Between Potency of CYP3A Inducer and Plasma 4β-Hydroxycholesterol in Healthy Subjects.

The objectives of this analysis were to establish the exposure‐response relationship between plasma rifampicin and 4β‐hydroxycholesterol (4βHC) concentration and to estimate the effect of weak, moderate, and potent CYP3A induction. Plasma rifampicin and 4βHC concentration‐time data from a drug‐drug interaction study with rifampicin 600 mg were used for model development. An indirect response model with an effect compartment described the relationship between rifampicin and 4βHC concentrations. The model predicted that the equilibration t1/2 and 4βHC t1/2 were 72.8 and 142 hours, respectively. EM50 and Emax of rifampicin induction were 32.6 μg and 8.39‐fold, respectively. The population PK‐PD model was then used to simulate the effects of rifampicin 10, 20, and 100 mg on plasma 4βHC for up to 21 days, in which rifampicin 10, 20, and 100 mg were used to represent weak, moderate, and strong inducers, respectively. The model‐predicted median (5th, 95th percentiles) 1.13 (1.04, 1.44)‐, 1.28 (1.10, 1.71)‐, and 2.10 (1.45, 3.49)‐fold increases in plasma 4βHC after 14‐day treatment with rifampicin 10, 20, and 100 mg, respectively. A new drug candidate can likely be classified as a weak, moderate, or strong inducer if baseline‐normalized plasma 4βHC increases by <1.13‐, 1.13‐ to 2.10‐, or >2.10‐fold, respectively, after 14 days of dosing.

Effect of food on the oral bioavailability of amlodipine/valsartan and amlodipine/valsartan/hydrochlorothiazide fixed dose combination tablets in healthy subjects

A double fixed dose combination of amlodipine/valsartan and triple fixed dose combination of amlodipine/valsartan/HCTZ tablets have been developed to treat patients with moderate‐to‐severe hypertension. Here, we present the effect of food on the oral bioavailability of these two fixed dose combination tablets from two separate clinical studies in healthy subjects. Single oral doses of amlodipine/valsartan (10/160 mg) and amlodipine/valsartan/HCTZ (10/320/25 mg were administered under fasted or fed conditions. Blood samples were collected in both studies to determine the pharmacokinetic parameters of amlodipine, valsartan, and/or HCTZ using non‐compartmental analysis. Following amlodipine/valsartan administration, the geometric mean ratios (GMRs, 90% CI) of AUC0–∞ and Cmax were 1.09 (1.05–1.13) and 1.03 (0.97–1.09) for amlodipine, and 0.94 (0.81–1.10) and 0.86 (0.73–1.02) for valsartan, respectively. Following amlodipine/valsartan/HCTZ administration, the GMRs (90%CI) of AUC0‐∞ and Cmax were 1.09 (1.04–1.15) and 1.11 (1.05–1.08) for amlodipine, 1.14 (0.99–1.31) and 1.12 (0.98–1.29) for valsartan, and 1.09 (1.02–1.16) and 0.86 (0.79–0.93) for HCTZ, respectively. Considering the sample size and pharmacokinetic variability associated with analytes, these study results indicate that food effect is minimal or none when fixed dose combination tablets are administered with food. In conclusion, both fixed dose combination tablets can be administered without regards to meals.

Pharmacokinetics and pharmacodynamics of aliskiren/hydrochlorothiazide single-pill combination tablets and free combination of aliskiren and hydrochlorothiazide.

Single‐pill combinations (SPCs) of complementary antihypertensive agents provide patients with a simple and effective treatment regimen. To ensure that the efficacy and safety of an SPC is the same as that for the individual drugs administered together (free combination), SPC and free‐combination formulations must be shown to be bioequivalent. Three open‐label, randomized studies compared the pharmacokinetics of SPC tablets of the direct renin inhibitor aliskiren and hydrochlorothiazide (HCT), at doses of 150/25, 300/12.5, and 300/25 mg, with the corresponding free combinations in healthy volunteers. Data from 2 randomized, double‐blinded studies of patients with hypertension were used to assess inhibition of plasma renin activity (PRA) by the aliskiren/HCT 300/25 mg SPC and the free combination. At all dose combinations, aliskiren and HCT systemic drug exposure was similar when administered as an SPC or free combination, indicating bioequivalence. Aliskiren/HCT 300/25 mg SPC inhibited PRA to the same extent as the free combination. HCT alone increased PRA through activation of the renin‐angiotensin system; aliskiren prevented this diuretic‐induced increase to the same extent when administered as the free combination or as the SPC. In conclusion, aliskiren/HCT SPCs are pharmacokinetically and pharmacodynamically bioequivalent to aliskiren and HCT in free combination.